Summary of medicine characteristics - INSULATARD FLEXPEN 100 INTERNATIONAL UNITS/ML SUSPENSION FOR INJECTION IN PRE-FILLED PEN
1 NAME OF THE MEDICINAL PRODUCT
Insulatard FlexPen 100 international units/ml suspension for injection in prefilled pen.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Insulatard InnoLet/Insulatard FlexPen
1 pre-filled pen contains 3 ml equivalent to 300 international units. 1 ml suspension contains 100 international units isophane (NPH) insulin human* (equivalent to 3.5 mg).
*Human insulin is produced in Saccharomyces cerevisiae by recombinant DNA technology.
Excipient with known effect:
Insulatard contains less than 1 mmol sodium (23 mg) per dose, i.e. Insulatard is essentially ‘sodium-free’.
For the full list of excipients, see section 6.1.
Suspension for injection.
The suspension is cloudy, white and aqueous.
4.1 Therapeutic indications
Insulatard is indicated for treatment of diabetes mellitus.
4.2 Posology and method of administrationPosology
The potency of human insulin is expressed in international units.
Insulatard dosing is individual and determined in accordance with the needs of the patient. The physician determines whether one or several daily injections are necessary. Insulatard may be used alone or mixed with fast-acting insulin. In intensive insulin therapy the suspension may be used as basal insulin (evening and/or morning injection) with fast-acting insulin given at meals. Blood glucose monitoring is recommended to achieve optimal glycaemic control.
The individual insulin requirement is usually between 0.3 and 1.0 international unit/kg/day.
Adjustment of dose may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.
Special , populations
Elderly (> 65 years old)
Insulatard can be used in elderly patients.
In elderly patients, glucose monitoring should be intensified and the insulin dose adjusted on an individual basis.
Renal and hepatic impairment
Renal or hepatic impairment may reduce the patient’s insulin requirements. In patients with renal or hepatic impairment, glucose monitoring should be intensified and the human insulin dose adjusted on an individual basis.
Paediatric population
Insulatard can be used in children and adolescents.
Transfer from other insulin medicinal products
When transferring from other intermediate or long-acting insulin medicinal products, adjustment of the Insulatard dose and timing of administration may be necessary.
Close glucose monitoring is recommended during the transfer and in the initial weeks thereafter (see section 4.4).
Insulatard is a human insulin with gradual onset and long duration of action.
Insulatard is administered subcutaneously by injection in the thigh, the abdominal wall, the gluteal region or the deltoid region. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see sections 4.4 and 4.8). Insulin suspensions are never to be administered intravenously. Injection into a lifted skin fold minimises the risk of unintended intramuscular injection.
The needle should be kept under the skin for at least 6 seconds to make sure the entire dose is injected. Subcutaneous injection into the thigh results in a slower and less variable absorption compared to the other injection sites. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.
Insulin suspensions are not to be used in insulin infusion pumps.
For detailed user instructions, please refer to the package leaflet.
Insulatard vial (40 international units/ml)/Insulatard vial (100 international units/ml)
Administration with a syringe
Insulatard vials are for use with insulin syringes with a corresponding unit scale.
Insulatard Penfill
Administration with an insulin delivery system
Insulatard Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles. Insulatard Penfill is only suitable for subcutaneous injections from a reusable pen. If administration by syringe is necessary, a vial should be used.
Insulatard InnoLet
Administration with InnoLet
Insulatard InnoLet is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm. InnoLet delivers 150 units in increments of 1 unit. Insulatard InnoLet is only suitable for subcutaneous injections. If administration by syringe is necessary, a vial should be used.
Insulatard FlexPen
Administration with FlexPen
Insulatard FlexPen is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm. FlexPen delivers 1–60 units in increments of 1 unit. Insulatard FlexPen is only suitable for subcutaneous injections. If administration by syringe is necessary, a vial should be used.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Before travelling between different time zones, the patient should seek the doctor’s advice since this may mean that the patient has to take the insulin and meals at different times.
Hyperglycaemia
Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. Usually, the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath. In type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.
Hypoglycaemia
Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycaemia.
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. In case of hypoglycaemia or if hypoglycaemia is suspected, Insulatard must not be injected. After stabilisation of the patient’s blood glucose, adjustment of the dose should be considered (see sections 4.8 and 4.9).
Patients whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia and should be advised accordingly. Usual warning symptoms may disappear in patients with longstanding diabetes.
Concomitant illness, especially infections and feverish conditions, usually increases the patient’s insulin requirement. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland can require changes in the insulin dose.
When patients are transferred between different types of insulin medicinal products, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin.
Transfer from other insulin medicinal products
Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (animal insulin, human insulin or insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in a need for a change in dose. Patients transferred to Insulatard from another type of insulin may require an increased number of daily injections or a change in dose from that used with their usual insulin medicinal products. If an adjustment is needed, it may occur with the first dose or during the first few weeks or months.
Injection site reactions
As with any insulin therapy, injection site reactions may occur and include pain, redness, hives, inflammation, bruising, swelling and itching. Continuous rotation of the injection site within a given area reduces the risk of developing these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of Insulatard.
Skin and subcutaneous tissue disorders
Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site from an affected to an unaffected area, and dose adjustment of antidiabetic medications may be considered.
Combination of Insulatard with pioglitazone
Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind if treatment with the combination of pioglitazone and Insulatard is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.
Avoidance of accidental mix-ups/medication errors
Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between Insulatard and other insulin products.
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
4.5 Interaction with other medicinal products and other forms of interaction
A number of medicinal products are known to interact with glucose metabolism.
The following substances may reduce the patient’s insulin requirement:
Oral antidiabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulfonamides.
The following substances may increase the patient’s insulin requirement: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.
Beta-blockers may mask the symptoms of hypoglycaemia.
Octreotide/lanreotide may either increase or decrease the insulin requirement.
Alcohol may intensify or reduce the hypoglycaemic effect of insulin.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no restrictions on treatment of diabetes with insulin during pregnancy, as insulin does not pass the placental barrier.
Both hypoglycaemia and hyperglycaemia, which can occur in inadequately controlled diabetes therapy, increase the risk of malformations and death in utero. Intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy.
Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements normally return rapidly to pre-pregnancy values.
Breast-feeding
There is no restriction on treatment with Insulatard during breast-feeding.
Insulin treatment of the nursing mother presents no risk to the baby. However, the Insulatard dose may need to be adjusted.
Fertility
Animal reproduction studies with human insulin have not revealed any adverse effects on fertility.
4.7 Effects on ability to drive and use machines
The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia while driving. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.
4.8 Undesirable effects
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, intermediate-acting, insulin (human). ATC code: A10AC01.
Mechanism of action and pharmacodynamic effects
The blood glucose lowering effect of insulin is due to the facilitated uptake of glucose following binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.
Insulatard is a human insulin with gradual onset and long duration of action.
Onset of action is within m hours, reaches a maximum effect within 412 hours and the entire duration of action is approximately 24 hours.
5.2 Pharmacokinetic properties
Insulin in the blood stream has a half-life of a few minutes. Consequently, the time-action profile of an insulin preparation is determined solely by its absorption characteristics.
This process is influenced by several factors (e.g. insulin dose, injection route and site, thickness of subcutaneous fat, type of diabetes). The pharmacokinetics of insulin medicinal products are therefore affected by significant intra- and inter-individual variation.
Absorption
The maximum plasma concentration of the insulin is reached within 218 hours after subcutaneous administration.
Distribution
No profound binding to plasma proteins, except circulating insulin antibodies (if present) has been observed.
Metabolism
Human insulin is reported to be degraded by insulin protease or insulindegrading enzymes and possibly protein disulfide isomerase. A number of cleavage (hydrolysis) sites on the human insulin molecule have been proposed; none of the metabolites formed following the cleavage are active.
Elimination
The terminal half-life is determined by the rate of absorption from the subcutaneous tissue. The terminal half-life (t%) is therefore a measure of the absorption rather than of the elimination per se of insulin from plasma (insulin in the blood stream has a t% of a few minutes). Trials have indicated a t% of about 5–10 hours.
5.3 Preclinical safety data
5.3 Preclinical safety dataNon-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
6.1
Zinc chloride
Glycerol
Metacresol
Phenol
Disodium phosphate dihydrate
Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Protamine sulfate
Water for injections
6.2 Incompatibilities
Insulin medicinal products should only be added to compounds with which it is known to be compatible. Insulin suspensions should not be added to infusion fluids.
6.3 Shelf life
Before opening: 30 months.
Insulatard Penfill/Insulatard InnoLet/Insulatard FlexPen
During use or when carried as a spare: The product can be stored for a maximum of 6 weeks. Store below 30°C.
6.4 Special precautions for storage
Before opening: Store in a refrigerator (2°C – 8°C). Do not freeze.
Insulatard InnoLet/Insulatard FlexPen
During use or when carried as a spare: Store below 30°C. Do not refrigerate or freeze.
Keep the pen cap on the pen in order to protect from light.
6.5 Nature and contents of container
Insulatard InnoLet/Insulatard FlexPen
Cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure (bromobutyl/polyisoprene) containing 3 ml of suspension in a pre-filled multidose disposable pen made of polypropylene. The cartridge contains a glass ball to facilitate resuspension.
Pack sizes of 1, 5 and 10 pre-filled pens. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalAfter removing Insulatard vial, cartridge or pre-filled pen from the refrigerator, it is recommended to allow the Insulatard vial, cartridge or prefilled pen to reach room temperature before resuspending the insulin as instructed for first time use.
Do not use this medicinal product if you notice that the resuspended liquid is not uniformly white and cloudy.
Insulatard which has been frozen must not be used.
The patient should be advised to discard the needle and syringe after each injection.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Needles, syringes, cartridges and pre-filled-pens must not be shared.
The cartridge must not be refilled.
7 MARKETING AUTHORISATION HOLDER
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark